Recent reports of an increase in possible treatment failure of azithromycin for Chlamydia trachomatis (Ct) and Mycoplasma genitalium (Mg) call for a better understanding of the origin of these repeat infections, so that providers can more efficiently target their treatment approach. For example if treatment failure is the origin, better medications are needed; if re-exposure to an untreated partner, better partner treatment strategies are needed; if exposure to a new partner, rescreening is indicated. Our preliminary data showed that the likely source of repeat infections among heterosexual men with Ct is multi-causal and treatment failure was substantial. These classifications, however, were based on self-reported sexual histories which may have over- estimated treatment failure. Genotyping data could provide a more objective method for classifying, but methodological issues with genotype-informed studies have made the origins of repeat infections difficult to interpret. We focus on heterosexual men, not just because their repeat infection rates are high, but because of their influence on women's health. Several decades of female-targeted interventions have failed to reduce the Ct epidemic. Clearly, interventions must also target men, particularly those with repeated infections, who may be core transmitters. We will also examine Mg, since there is mounting evidence that it is an important source of reproductive health morbidity and high rates of repeat infection have been documented. The goal of the study is to reduce early repeat infections with Ct and/or Mg among heterosexual men. Aim 1: To quantify the likely origins of early repeat infections with Ct and/or Mg among heterosexual men - We will combine data from electronic sexual diaries, test of cure computer assisted interviews and state-of-the-art genotyping of Ct and/or Mg to calculate the most likely source of repeat infection at test-of-cure. We hypothesize that there are multiple origins of repeat infection and that treatment failure is substantial (i.e. > 6%), which requires a re-evaluation of the present treatment guidelines. Aim 2: To conduct in-depth exploration of the origins of repeat Ct and/or Mg infections and explore adaptations of EPT and/or rescreening among heterosexual men. In-depth interviews will be conducted with men who do (n=30) and do not (n=30) have repeat Ct and/or Mg infections to enhance our understanding of the subtle, nuanced aspects of risk behaviors and contexts that lead or do not lead to repeat infections. These data will allow for the development of more gender appropriate counseling and interventions to reduce repeat infections among heterosexual men. To achieve these aims, we extend work started in our R56. Men attending two urban STD clinics (n=4777) will be screened for Ct/ Mg. Men with either organisms (~2327), will complete a weekly electronic sexual diaries, and return for a test of cure screening and interview 4 weeks post baseline. Specimens from men with repeat Ct and/or Mg infections (200 for each) will be genotyped. This research fits well within NIAID's goals of reducing health disparities/providing more effective STD treatment.